Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors

Derek A. Wainwright, Sadhak Sengupta, Yu Han, Maciej S. Lesniak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an average survival time of 15 months. Previously, we and others demonstrated that CD41FoxP31 regulatory T cells (Tregs) infiltrate human GBM as well as mouse models that recapitulate malignant brain tumors. However, whether brain tumor-resident Tregs are thymus-derived natural Tregs (nTregs) or induced Tregs (iTregs), by the conversion of conventional CD41 T cells, has not been established. To investigate this question, we utilized the i.c. implanted GL261 cell-based orthotopic mouse model, the RasB8 transgenic astrocytoma mouse model, and a human GBM tissue microarray. We demonstrate that Tregs in brain tumors are predominantly thymus derived, since thymectomy, prior to i.c. GL261 cell implantation, significantly decreased the level of Tregs in mice with brain tumors. Accordingly, most Tregs in human GBM and mouse brain tumors expressed the nTreg transcription factor, Helios. Interestingly, a significant effect of the brain tumor microenvironment on Treg lineage programming was observed, based on higher levels of brain tumor-resident Tregs expressing glucocorticoid- induced tumor necrosis factor receptor and CD103 and lower levels of Tregs expressing CD62L and CD45RB compared with peripheral Tregs. Furthermore, there was a higher level of nTregs in brain tumors that expressed the proliferative marker Ki67 compared with iTregs and conventional CD41 T cells. Our study demonstrates that future Treg-depleting therapies should aim to selectively target systemic rather than intratumoral nTregs in brain tumor-specific immunotherapeutic strategies.

Original languageEnglish (US)
Pages (from-to)1308-1323
Number of pages16
JournalNeuro-oncology
Volume13
Issue number12
DOIs
StatePublished - Dec 2011

Keywords

  • Brain cancer
  • CD25
  • CD4
  • FoxP3
  • GBM
  • Glioblastoma
  • Glioma
  • RasB8
  • Regulatory T cells
  • Tregs.

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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